Immunology. Guilty by association.

evant antigen. These data suggest a model in which populations of tissue-specifi c Tregs arise during thymic development and then accumulate within those peripheral tissues on the basis of antigen recognition (see the fi gure). As tumors develop, these preexisting tissue-resident Tregs are recruited into and/or expanded within the tumor microenvironment, potentially allowing them to exert local immunosuppression. Thus, recognition of tissue-restricted antigens can play a central role in Treg infiltration into tumors (and likely their function), even though the Tregs and antigens exist independent of tumor formation. This study raises additional questions that bear on the role of Tregs and cancer development. For example, it would be interesting to know whether the tissue-specifi c Tregs found in the prostate tumor actively suppress antitumor immune responses. Likewise, what is their function in non–tumor-bearing animals? Given that this study makes a convincing case for tissue-resident Tregs in this genetically engineered mouse model of prostate cancer, are these findings generalizable to other tumor types and settings? In particular, it will be important to test whether natural, tissue-specifi c Tregs are the predominant population in tumors derived from other tissues and in tumors with higher mutation rates (i.e., carrying more tumor neoantigens) or increased expression of tumor-specifi c antigens. Indeed, previous work suggested that tumor-infi ltrating Treg populations would be a mixture of cells specifi c for tumor-specifi c neoantigens and tumor-associated antigens ( 7, 8). It will also be interesting to determine whether Tregs that infi ltrate distant metastases are specifi c for antigens expressed in the original tumor tissue or the tissue in which the metastasis seeded. Metastatic disease accounts for more than 80% of all cancer deaths, so therapies that target Tregs in both metastases and primary tumors will likely be more effi cacious in treating disease. Understanding the broader set of mechanisms that govern the localization and function of Tregs in cancer will help guide the development of appropriate therapies that target this important class of cells in cancer patients.